IT8921990A1 - N, N'-DI- (TRIMETHOXYBENZOIL) PIPERAZINE 2-METHOXYCARBONIL SUBSTITUTE PROCEDURE TO PREPARE THE SAME AND THERAPEUTIC COMPOUNDS THAT CONTAIN THEM. - Google Patents

Description

TEXT OF THE DESCRIPTION

This invention relates to piperazine derivatives having the general formula I:

where Y represents

and Z represents

a substituent A wherein A represents a linear or branched alkyl chain having from 1 to 17 carbon atoms; a cycloalkyl group having from 5 to 10 carbon atoms or a group having the general formula:

in which n? zero or an integer from 1 to 5 and each of R, R, R, R and R, independently, represents a hydrogen, chlorine or bromine atom, a trifluoromethyl, trifluoromethylthio or trifluoromethoxy, methyl or methoxy group

or an NH-A substituent in which A? as defined above. The invention also relates to a process for preparing the compounds of formula I, said process comprising bringing a compound of formula I to react

when Z = A or A-N = C = 0

when Z = NH-A where A? as defined above, with?,? '- dibenzyl 2-hydroxymethyl piperazine. The reaction is conveniently carried out in the presence of triethylamine, in an aprotic solvent, such as diethyl ether, tetrahydrofuran, benzene or toluene, at room temperature, when Z represents

or in benzene or toluene, at 80? C, when Z represents A-N = C = 0.

The corresponding trisubstituted piperazine obtained, of formula II:

it is then subjected to hydrogenolysis in the presence of Pd / carbon (in ethanol) leading to the monosubstituted piperazine of formula III

which is di-N-substituted by treatment with 3,4,5-trimethoxybenzoyl chloride, in benzene, in the presence of triethylamine, at room temperature to provide I.

The invention ultimately relates to therapeutic compositions containing one of the compounds I, as an active ingredient. These compounds are active as anti-ischemic and anti-inflammatory in various fields, for example in kidney disorders.

EXAMPLE 1

Stage A

Preparation of N, N'-dibenzyl 2-cyclohexylcarbonyloxymethyl piperazine (II, Z

A solution of 2 g (6.8 mmol) of?,? '- dibenzyl 2-hydroxymethyl piperazine in 30 ml of dry benzene and 1 ml of triethylamine? was added dropwise to 1.1 g (6.8 mmol) of cyclohexane carbonyl chloride in 10 ml of benzene. After stirring overnight, at room temperature, the solvents were removed under reduced pressure and the crude residue treated with CHCl? been washed with 0, diluted with NaH-CO then with H 0. The organic layer? it was then dried (MgSO4), evaporated and chromatographed on a silica gel column using ethyl ether / petroleum ether (10:90, by volume) as eluent. This purification resulted in 1.87 g (68%) of the title compound as an oil.

Stage B

Preparation of 2-cyclohexylcarbonyloxymethyl piperazine

A solution of 1.5 g (3.7 mmol) of the compound prepared in step A and 50 mg of Pd (10%) / charcoal in 50ml of ethanol? been treated with under pressure of 2.8 bar under? tour at 40? C for one night. After filtration the ethanol? was evaporated under reduced pressure and the crude residue purified on a silica gel column using MeOH / CHCl (5:95, by volume) as eluent. This operation yielded 0.75 g (90%) of the title compound as a very hygroscopic product.

Stage C

Preparation of N, N, -di- (3, 4,, 5, -trimethoxybenzoyl) -2-cyclohexylcarbonyloxymethyl piperazine

A solution of 0.5 g (2.2 mmol) of the compound prepared in step B in 30 ml of dry benzene and 1.5 ml of triethylamine? was added dropwise to 1 g (4.6 mmol) of 3,4,5-trimethoxybenzoyl chloride in 10 ml of dry benzene. The mixture ? was kept under stirring overnight at room temperature. Excess of acyl chloride? it was then decomposed by adding 1 ml of EtOH. After evaporation of the solvents under reduced pressure, the residue? was treated with CHCl, washed with 0, diluted with NaHCO, then with H 0. After drying (MgSO) and evaporation of the chloroform, a silica gel column purification using MeOH / CHCl3 (0.5: 99.5, in volume) yielded 1.1 g (74%) of the title compound as a wax.

EXAMPLE 2

N, N '? Of? (3', 4 ', 5'? Trimethoxybenzoyl)? 2? Tert? Butyl carbons? loss imeti l piperazine Z = C (CH3) 3

The compound of the title? was obtained as described in Example 1, stages A, B, C, but starting from 2,2-dimethylpropanoyl chloride instead of cyclohexanecarbon chloride in the form of a waxy compound.

EXAMPLE 3

N, N'-di- (3 ', 4', 5'-trimethoxybenzoyl)? 2? N-butanoyloxymethyl piperazine Z = (CH) CH

The compound of the title? was obtained as described in Example 1, stages A, B, C, but starting from n-butanoyl chloride in the form of oil.

EXAMPLE 4

N, N'-di- (3 ', 4', 5'-trimethoxybenzoyl) -2-n-octanoyloxymethyl piperazine Z = (CH) CH

The compound of the title? was obtained as described in example 1, steps A, B, C, but starting with n-octanoyl chloride. Viscous compound.

EXAMPLE 5

N, N '-di- (3', 4 ', 5'-trimethoxybenzoyl) -2-n-decanoyloxymethyl piperazine Z = (CH) CH

The compound of the title? was obtained as described in example 1, stages A, B, C, but starting from n-decanoyl chloride. Viscous compound.

EXAMPLE 6

N, N '? Of? (3 ', 4', 5'-trimethoxybenzoyl) -2-octadecanoyloxymethyl piperazine Z = (CH2) CH3

The compound of the title? was obtained as described in Example 1, stages A, B, C, but starting from octadecanoyl chloride. Viscous oil.

EXAMPLE 7

N, N'-di ~ (3 ', 4', 5 ', - trimethoxybenzoi l) -2-orthochlorobenzoloxymethyl piperazine

The compound of the title? was obtained as described in example 1, stages A, B, C, but starting from 2-chlorobenzoyl chloride. Oily product.

EXAMPLE 8

Stage A

Preparation of N, N'-dibenzyl 2-N "- (n-butyl) -carbamoyloxymethyl piperazine

A mixture of 10 g (34 mmol) of?,? '- dibenzyl 2-hydroxymethyl piperazine, 10 g (102 mmol) of n-butyl-isocyanate and 15 ml of triethylamine in 100 ml of dry benzene? was brought to reflux under stirring for 48 hours. After evaporation of the solvents, the crude residue? been treated with CHCl, washed with H 0, diluted with NaHCO and then with H 0. The chloroform layer? was dried (MgSO4), concentrated under reduced pressure and purified on a silica gel column using diethyl ether / light petroleum (10:90, by volume) as eluent to yield 11.7 g (87%) of the title compound as oil.

Stages B and C

The compound of the title? been obtained as described in example 1, stages B and C. It is? presented in the form of white crystals, melting point 90 ° C.

EXAMPLE 9

?,?'-from? (3 ', 4', 5'-trimethoxybenzoyl) -2-N "- (3 ', 4', 5'-trimetoes hyphenyl) -carbamoyloxymethyl piperazine.

The compound of the title? been obtained as described in example 8 for stage A, but starting from quantities? equimolar of?,? '- dibenzyl 2-hydroxymethyl piperazine and 3,4,5-trimethoxyphenyl isocyanate in place of n-butyl isocyanate. Stages B and C were as in example 1, stages B and C. The compound obtained was a light yellow solid, melting point = 122 ° C.

According to the same procedure as described in example 1, stages A, B, C, the following compounds were prepared (only the modifications of the 1 H NMR spectra are provided):

EXAMPLE 10

N, N'-di- (3 ', 4', 5, -trimethoxybenzoyl) -2- {2, -ethyl) -butanoyloxymethyl piperazine

melting point = 170.2? C. 1 H NMR? ppm: 2.12 (quintet,

EXAMPLE 11

N, N1? Di- (3 ', 4', 54-trimethoxybenzoyl)? 2-n? Hexanoyloxymethyl piperazine Z = - (CH2) 4 CH3

waxy solid, 1 H NMR ppm: 2.27 (m, 2H, CH2 C = 0), 1.51 (m, 2H, CH2 -C-C = 0), 1.25 (m, 4H, CH2), 0, 77 (t, 3H, CH3).

EXAMPLE 12

N, N'-di- (3 ', 4', 5'-trimethoxybenzoyl) -2-acetyloxymethyl piperazine Z = - CH3

melting point = 59? C. 1 H NMR? ppm: 1.93 (s, 3H, CH3 C = O).

EXAMPLE 13

N, N'-di- (3 ', 4', 5'-trimethoxybenzoyl) -2-tert-butyl acetyloxymethyl piperazine Z = - CH2 C (CH3) 3

melting point: 86.6? C. 1 H NMR? ppm: 2.05 (s, 2H, CH2 C = 0), 0.92 (s, 9H, CH3).

According to the same procedure as described in example 8, stages A, B, C, the following compounds were prepared (only the modifications of the 1 H NMR spectra are provided):

EXAMPLE 14

N, N? -Di (3 ', 4', 5 ', - trimethoxybenzoyl) -2-N "- (1? -Ethyl) -propyl carboxymethyl piperazine

melting point = 90.2? C. 1 H NMR? ppm: 3.55 - 2.92 (m, 5H, CH2 NC = 0 CH N COO), 1.37 (m, 4H, CH2 CH), 0.82 (t, 6H, CH3).

EXAMPLE 15

N, N? -Di- (3 ', 4', 5'-trimethoxybenzoyl) -2-N "-tert-butyl carboxymethyl piperazine Z = - NH-C (CH3) 3

viscous compound. 1 H NMR d ppm: 1.20 (s, 9H, CH3).

EXAMPLE 16

N, N? -Di- (3 ', 4', 5'-trimethoxybenzoyl) -2-N "-tert-amyl caramoyloxymethyl piperazine Z =? NH? CH2 -C (CH3) 3

melting point = 80 ° C. 1 H NMR? ppm: 0.80 (s, 9H, CH3).

EXAMPLE 17

N.N? -Di- (3 ', 4', 5, '- trimethoxybenzoyl) -2-N ,, - orthochlorophenyl caramoyloxymethyl piperazine

fieione point = 115? C.1 H NMR? ppm: 7.3 and 6.7 (2 s.

4H, C6 H4), 6.67 - 6.42 (m, 4H, C6 H2).

EXAMPLE 18

?,? '? di- (3?, 4', 5'-trimetohexibenzoi 1) -2-N "- (1? methyl) -butyl caramoyloxymethyl piperazine

melting point = 78? C. 1 H NMR? ppm: 1.27 (m, 4H, CH2), 1.02 (d, 3H, CH3 CH), 0.85 (T, 3H, CH3).

EXAMPLE 19

?,? '? di- (3', 4 ', 5'-trimethoxybenzoyl) -2-N "- (l', 2 ', 2? -trimethylpropyl caramoyloxymethyl piperazine

melting point = 86? C. 1 H NMR? ppm: 0.92 (m, 3H, CH3 CH), 0.79 (s, 9H, CH3 C).

EXAMPLE 20

N, N'-di- (3 ', 4', 5'-trimethoxybenzoyl) -2-N "- (3'-methyl) -butyl carboxyloxymethyl piperazine

melting point = 71? C. 1 H NMR? ppm: 2.17 - 1.80 (m, 1H,

CH (CH3) 2 1.27 (m, 2H, CH2 0.80 (d, 6H, CH3

EXAMPLE 21

N, N '? Di? (3', 4 ', 5'? Trimethoxybenzoyl)? 2-N "? (1 ', 3'-dimethyl)? Butyl caramoyloxymethyl piperazine

melting point = 76 ° C. 1 H NMR? ppm: 2.35 - 1.91 (m, 1H, CH (CH3) 2), 1.18 (m, 2H, CH2), 098 (d, 3H, CH3 -C-N), 0.78 (d, 6H , CH3).

EXAMPLE 22

N, N'-di- (3 ', 4', 5, -trimethoxybenzoyl) -2-N "- (2, -methyl) -butyl cartoamoyloxymethyl piperazine

melting point = 70 ° C. 1 H NMR? ppm: 1.70 (m, 1H, CH), 1.22 (m, 2H, CH), 0.85 (m, 6H, CH).

TOXICOLOGY

The compounds were administered orally to mice for DL determination. For all the compounds of the invention the DL was higher than 700 mg / kg.

PHARMACOLOGY

A proof of the pharmaceutical interest of the compounds of the invention? was obtained with the following pharmaceutical experimentation:

Inhibition of platelet aggregation on New Zealand rabbits

The experimentation? was conducted on platelets with plasma from New Zealand rabbits.

Blood samples were taken from the auricular artery and placed in a citrate buffer (3.8%, pH 7.4); the blood ? was further centrifuged for 15 minutes at 1200 rpm.

THE proven champion? been prepared in DMS0, then pour? on platelet-enriched plasma for 1 minute, then? A 2.5 nM dose of PAF was added.

The determination is carried out on a Cronolog Coultronics device which determines the percentage of transmission corresponding to the maximum height of the peak before disaggregation.

The percentage change in inhibition versus transmission percentage is calculated (control: pure DMSO).

This method? been described in detail in LABORATORY INVESTIGATIONS, Vol. 41, No. 3, p. 275, 1979, JEAN-PIERRE CAZENAVE, Dr. MED., JACQUES BENVENISTE, DR. MED., AND J. FRASER MUSTARD, M.D., "Aggregation of rabbits platelets by platelet-ac tivating factor is independent of th? Release reaction and th? Arachidonate pathway and inhibited by membrane-active drugs".

The results demonstrate that the compounds inhibit the 2.5 nM-induced aggregation of PAF. Nine tests performed on 9 different rabbits allowed to calculate the IC value of the different compounds using the linear regression test. Values for the IC on platelets were found in the following terms:

PRESENTATION OF DOSAGE

In human therapy the active doses are 1-50 mg / kg per day in oral administration (tablets and gelatin capsules, containing for example 50 mg or 100 mg per unit dose) or 0.1 - 5 mg / kg in i.v. administration. (unit dose of 5-100 mg in single ampoules).

Claims (3)

CLAIMS 1. Derivatives of piperazine having the general formula I: where Y represents and Z represents a substituent A wherein A represents a linear or branched alkyl chain having from 1 to 17 carbon atoms; a cycloalkyl group having from 5 to 10 carbon atoms or a group having the general formula: in which n? zero or an integer from 1 to 5 and each of the R, R, R, R and R groups independently, represents a hydrogen, chlorine or bromine atom, a trifluoromethyl, trifluoromethyl or trifluoromethoxy group, a methyl or methoxy group or an NH-A substituent in which A? as defined above. 2. Process of preparation of the compounds of claim 1, said process comprising the steps of a) causing a compound of formula when Z = A or A-N = C = 0 when Z? NH? A, where A? as defined above, with?,? '- dibenzyl 2-hydroxymethyl piperazine, the reaction being carried out in the presence of triethylamine, in an aprotic solvent, at room temperature, when Z represents or in benzene or toluene, at 80 ° C, when Z represents A-N = C = 0 b) subjecting to hydrogenolysis the corresponding trisubstituted piperazine, of formula II: in the presence of Pd / carbon (in ethanol) forming the monosubstituted piperazine of formula III: c) treating said compound with 3,4,5-trimethoxybenzoyl chloride in benzene in the presence of triethylamine, at room temperature, to provide piperazine derivatives of general formula I. 3. A therapeutic composition comprising a quantity? effective of at least one compound according to claim 1, i.e., per unit dose, 50-100 mg for oral administration or 5-100 mg for intravenous administration, associated with the usual excipients for the chosen route of administration.